Thioglycoluril compound, and method for producing same

ABSTRACT

A novel monothioglycoluril compound and a novel dithioglycoluril compound. A thioglycoluril compound of the following Formula (1):(wherein X is an oxygen atom or a sulfur atom, and four Rs are each a hydrogen atom, a linear, branched, or cyclic alkyl group having a carbon atom number of 1 to 4, a phenyl group, a naphthyl group, a benzyl group, or a C3-9 alkyl group having at least one ether bond on the main chain).

This application is a Divisional of application Ser. No. 16/654,664,filed Oct. 16, 2019, which is a Divisional of application Ser. No.16/330,071, filed Mar. 1, 2019 (now U.S. Pat. No. 10,590,141), which isa national stage of PCT/JP2017/029980, filed Aug. 22, 2017, which claimspriority to Japanese Application No. 2016-171647, filed Sep. 2, 2016.The entire contents of the prior applications are hereby incorporated byreference herein in their entirety.

TECHNICAL FIELD

The present invention relates to a novel monothioglycoluril compound anda novel dithioglycoluril compound, and methods for producing thesecompounds.

BACKGROUND ART

Glycoluril compounds are heterocyclic compounds each having four ureanitrogen atoms in the ring structure. Glycoluril compounds havingvarious substituents on the urea nitrogen atoms have been produced andused as functional compounds.

For example, 1,3,4,6-tetrakis(methoxymethyl)glycoluril, which has fourmethoxymethyl groups in the molecule, is well known as a crosslinkingagent for epoxy resins (see Patent Document 1).

A glycoluril compound prepared by substitution of an oxygen atom with asulfur atom in the ring structure, for example, a monothioglycolurilcompound and a dithioglycoluril compound, have also been known. Amonothioglycoluril compound and a dithioglycoluril compound havingsubstituents on a urea nitrogen atom or a thiourea nitrogen atom and ona bridgehead carbon atom have been synthesized (see Non-Patent Documents1, 2, 3, and 4).

For example, Patent Document 2 discloses a method involving introductionof four methoxymethyl groups in one glycoluril molecule having nosubstituent. However, none of Patent Documents 1 and 2 and Non-PatentDocuments 1, 2, 3, and 4 describes a monothioglycoluril compound and adithioglycoluril compound in which the hydrogen atom on at least onenitrogen atom is substituted with an alkoxymethyl group such as amethoxymethyl group.

PRIOR ART DOCUMENTS Patent Documents

-   Patent Document 1: Japanese Patent Application Publication No.    2013-33276 (JP 2013-33276 A)-   Patent Document 2: Japanese Patent No. 3154819

Non-Patent Documents

-   Non-Patent Document 1: European Journal of Organic Chemistry, pp.    933-940 (2014)-   Non-Patent Document 2: Journal of Organic Chemistry, 62, 8834-8840    (1997)-   Non-Patent Document 3: Chemistry A European Journal, 21, 536-540    (2015)-   Non-Patent Document 4: Tetrahedron Letters, 56, 6085-6088 (2015)

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

A monothioglycoluril or dithioglycoluril compound having a plurality ofalkoxymethyl groups in the molecule (e.g., two or more alkoxymethylgroups in the molecule) is useful as, for example, a crosslinking agentfor epoxy resins. A monothioglycoluril or dithioglycoluril compound,which is prepared by substitution of at least one of two oxygen atomswith a sulfur atom in the ring structure of a glycoluril compound, hasoptical properties different from those of1,3,4,6-tetrakis(methoxymethyl)glycoluril. In particular, amonothioglycoluril compound, in which only one of the aforementioned twooxygen atoms is substituted with a sulfur atom, is expected to haveexcellent solubility in a solvent because of its low molecular symmetry.

The present invention has been made on the basis of the situationdescribed above, and an object of the present invention is to provide anovel monothioglycoluril compound and a novel dithioglycoluril compound.

Means for Solving the Problems

An aspect of the present invention is a thioglycoluril compound of thefollowing Formula (1):

(wherein X is an oxygen atom or a sulfur atom, and four Rs are each ahydrogen atom, a linear, branched, or cyclic alkyl group having a carbonatom number of 1 to 4, a phenyl group, a naphthyl group, a benzyl group,or a C₃₋₉ alkyl group having at least one ether bond on the main chain).

The thioglycoluril compound of Formula (1) is a monothioglycolurilcompound of the following Formula (2):

(wherein four Rs have the same meanings as defined above in Formula(1)).

The thioglycoluril compound of Formula (1) is a dithioglycolurilcompound of the following Formula (3):

(wherein four Rs have the same meanings as defined above in Formula(1)).

Another aspect of the present invention is a method for producing amonothioglycoluril compound, the method comprising a first step ofcausing a reaction between formaldehyde and a compound of the followingFormula (4a) in a basic aqueous solution, and then isolating a compoundof the following Formula (2a); and a second step of causing a reactionbetween the compound of the following Formula (2a) and an alcohol of thefollowing Formula (5) in an acidic solution containing the alcohol as asolvent, adding a basic aqueous solution to the resultant reactionmixture, and purifying the resultant product by silica gel columnchromatography for removal of impurities from the product, so as toproduce a monothioglycoluril compound of the following Formula (2b):

(wherein four R¹ _(s) are each a linear, branched, or cyclic alkyl grouphaving a carbon atom number of 1 to 4, a phenyl group, a naphthyl group,a benzyl group, or a C₃₋₉ alkyl group having at least one ether bond onthe main chain).

Still another aspect of the present invention is a method for producinga dithioglycoluril compound, the method comprising a first step ofcausing a reaction between formaldehyde and a compound of the followingFormula (4b) in a basic aqueous solution, and then isolating a compoundof the following Formula (3a); and a second step of causing a reactionbetween the compound of the following Formula (3a) and an alcohol of thefollowing Formula (5) in an acidic solution containing the alcohol as asolvent, adding a basic aqueous solution to the resultant reactionmixture, and washing the resultant product with water for removal ofimpurities from the product, so as to produce a dithioglycolurilcompound of the following Formula (3b):

(wherein four R¹s are each a linear, branched, or cyclic alkyl grouphaving a carbon atom number of 1 to 4, a phenyl group, a naphthyl group,a benzyl group, or a C₃₋₉ alkyl group having at least one ether bond onthe main chain).

Effects of the Invention

The thioglycoluril compound according to the present invention isproduced by substitution of the hydrogen atoms bonded to the fournitrogen atoms of thioglycoluril with a —CH₂—O—R group (wherein R hasthe same meaning as defined above in Formula (1)), and the compound is anovel sulfur-containing heterocyclic compound. A thioglycoluril compoundhaving two or more —CH₂—O—R groups (wherein R has the same meaning asdefined above) in the molecule is useful as, for example, a crosslinkingagent for epoxy resins. In particular,1,3,4,6-tetrakis(methoxymethyl)monothioglycoluril and1,3,4,6-tetrakis(methoxymethyl)dithioglycoluril, in which the hydrogenatoms on all the nitrogen atoms are substituted with a methoxymethylgroup, have excellent crosslinking performance.

1,3,4,6-Tetrakis(methoxymethyl)monothioglycoluril and1,3,4,6-tetrakis(methoxymethyl)dithioglycoluril, which contain a sulfuratom, are expected to have optical properties different from those of1,3,4,6-tetrakis(methoxymethyl)glycoluril. In particular,1,3,4,6-tetrakis(methoxymethyl)monothioglycoluril has an asymmetricmolecular structure and thus low molecular symmetry. Therefore, whenused as, for example, a crosslinking agent for epoxy resins,1,3,4,6-tetrakis(methoxymethyl)monothioglycoluril exhibits highersolubility in a solvent than conventional1,3,4,6-tetrakis(methoxymethyl)glycoluril.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows ¹H-NMR spectra of1,3,4,6-tetrakis(methoxymethyl)monothioglycoluril.

FIG. 2 shows ¹H-NMR spectra of1,3,4,6-tetrakis(methoxymethyl)dithioglycoluril.

FIG. 3 shows UV spectra of 1,3,4,6-tetrakis(methoxymethyl)glycoluril,1,3,4,6-tetrakis(methoxymethyl)monothioglycoluril, and1,3,4,6-tetrakis(methoxymethyl)dithioglycoluril.

MODES FOR CARRYING OUT THE INVENTION

The thioglycoluril compound of the present invention is amonothioglycoluril compound of the following Formula (2):

(wherein four Rs are each a hydrogen atom, a linear, branched, or cyclicalkyl group having a carbon atom number of 1 to 6, a phenyl group, anaphthyl group, a benzyl group, or a C₃₋₉ alkyl group having at leastone ether bond on the main chain).

The thioglycoluril compound of the present invention is adithioglycoluril compound of the following Formula (3):

(wherein four Rs have the same meanings as defined above in Formula(2)).

In the monothioglycoluril compound of Formula (2) and thedithioglycoluril compound of Formula (3), when four Rs are each alinear, branched, or cyclic alkyl group, the number of carbon atoms ofthe alkyl group is, for example, 1 to 12, preferably 1 to 4, mostpreferably 1. Thus, the most preferred alkyl group is a methyl group.

Preferred examples of the monothioglycoluril compound anddithioglycoluril compound of the present invention wherein four Rs areeach the aforementioned alkyl group include1,3,4,6-tetrakis(methoxymethyl)monothioglycoluril,1,3,4,6-tetrakis(ethoxymethyl)monothioglycoluril,1,3,4,6-tetrakis(propoxymethyl)monothioglycoluril,1,3,4,6-tetrakis(n-butoxymethyl)monothioglycoluril,1,3,4,6-tetrakis(methoxymethyl)dithioglycoluril,1,3,4,6-tetrakis(ethoxymethyl)dithioglycoluril,1,3,4,6-tetrakis(propoxymethyl)dithioglycoluril, and1,3,4,6-tetrakis(n-butoxymethyl)dithioglycoluril.

In the monothioglycoluril compound of Formula (2) and thedithioglycoluril compound of Formula (3), when R is an alkyl grouphaving at least one ether bond on the main chain, the number of carbonatoms of the alkyl group having at least one ether bond on the mainchain is, for example, 3 to 9, preferably 3 to 5, most preferably 4.

Preferred examples of the monothioglycoluril compound anddithioglycoluril compound of the present invention wherein four Rs areeach the aforementioned alkyl group having at least one ether bond onthe main chain include1,3,4,6-tetrakis((2-methoxyethoxy)methyl)monothioglycoluril,1,3,4,6-tetrakis((2-(2-methoxyethoxy)ethoxy)methyl)monothioglycoluril,1,3,4,6-tetrakis(((1-methoxypropan-2-yl)oxy)methyl)monothioglycoluril,1,3,4,6-tetrakis(((1-ethoxypropan-2-yl)oxy)methyl)monothioglycoluril,1,3,4,6-tetra(2,5,8,11-tetraoxadodecyl)monothioglycoluril,1,3,4,6-tetra(2,5,8,11,14-pentaoxapentadecyl)monothioglycoluril,1,3,4,6-tetrakis((2-methoxyethoxy)methyl)dithioglycoluril,1,3,4,6-tetrakis((2-(2-methoxyethoxy)ethoxy)methyl)dithioglycoluril,1,3,4,6-tetrakis(((1-methoxypropan-2-yl)oxy)methyl)dithioglycoluril,1,3,4,6-tetrakis(((1-ethoxypropan-2-yl)oxy)methyl)dithioglycoluril,1,3,4,6-tetra(2,5,8,11-tetraoxadodecyl)dithioglycoluril, and1,3,4,6-tetra(2,5,8,11,14-pentaoxapentadecyl)dithioglycoluril.

A monothioglycoluril compound of the following Formula (2b):

(wherein four R¹s are each a linear, branched, or cyclic alkyl grouphaving a carbon atom number of 1 to 6, a phenyl group, a naphthyl group,a benzyl group, or a C₃₋₉ alkyl group having at least one ether bond onthe main chain) can be produced by reacting1,3,4,6-tetramethylolmonothioglycoluril of the following Formula (2a):

with an alcohol, to thereby etherify the methylol groups of the1,3,4,6-tetramethylolmonothioglycoluril.

A dithioglycoluril compound of the following Formula (3b):

(wherein four R¹s are each a linear, branched, or cyclic alkyl grouphaving a carbon atom number of 1 to 6, a phenyl group, a naphthyl group,a benzyl group, or a C₃₋₉ alkyl group having at least one ether bond onthe main chain) can be produced by reacting1,3,4,6-tetramethyloldithioglycoluril of the following Formula (3a):

with an alcohol, to thereby etherify the methylol groups of the1,3,4,6-tetramethyloldithioglycoluril.

Methods of etherifying a methylol group have been known, and any knownmethod can be used in the present invention. The etherification methodmay be, for example, a method involving the use of an acid selected fromthe group consisting of hydrochloric acid, nitric acid, and sulfuricacid. The acid is used in an amount of preferably 0.1 equivalents to 1.0equivalent relative to a tetramethylolthioglycoluril compound.

The reaction solvent used for the aforementioned etherification is analcohol of the following Formula (5):R¹—OH   (5)(wherein R¹ has the same meaning as defined above in Formulae (2b) and(3b)).

The reaction temperature for etherification of atetramethylolthioglycoluril compound using any of the aforementionedacids may vary depending on the type of the reaction solvent used, andis generally 10° C. to 150° C. The reaction time must be varied with thereaction temperature, and is generally 1 hour to 48 hours.

After completion of the reaction, a base (e.g., an aqueous sodiumhydroxide solution) is added to the resultant reaction mixture foradjustment of the pH thereof, and the resultant reaction product isconcentrated, or dissolved in an appropriate solvent and separated byfiltration, to thereby yield a product containing a monothioglycolurilor dithioglycoluril compound of interest.

The resultant product is subjected to washing with a solvent such aswater, crystallization, or purification by, for example, silica gelcolumn chromatography, to thereby remove impurities from the product.

1,3,4,6-Tetramethylolmonothioglycoluril of Formula (2a) can be producedby reacting monothioglycoluril of the following Formula (4a):

with formaldehyde for methylolation of the hydrogen atoms bonded to thenitrogen atoms of the monothioglycoluril.

1,3,4,6-Tetramethyloldithioglycoluril of Formula (3a) can be produced byreacting dithioglycoluril of the following Formula (4b):

with formaldehyde for methylolation of the hydrogen atoms bonded to thenitrogen atoms of the dithioglycoluril.

Methods of methylolation of a hydrogen atom bonded to a nitrogen atomhave been known, and any known method can be used in the presentinvention. The methylolation method may be a method involving the useof, for example, a base selected from the group consisting of sodiumhydroxide and potassium hydroxide in an aqueous formaldehyde solution.The base is used in an amount of preferably 0.001 equivalents to 0.01equivalents relative to monothioglycoluril or dithioglycoluril.

The reaction solvent used for the aforementioned methylolation is water.

The reaction temperature for methylolation of a thioglycoluril compoundusing any of the aforementioned bases is 25° C. to 100° C. The reactiontime must be varied with the reaction temperature, and is generally 1hour to 24 hours.

EXAMPLES

The present invention will next be described by way of examples, but thepresent invention is not particularly limited to the examples.

Synthesis Example 1 Synthesis of Monothioglycoluril

Monothioglycoluril of Formula (4a) was synthesized according to themethod described in Non-Patent Document 1: European Journal of OrganicChemistry, pp. 933-940 (2014).

Synthesis Example 2 Synthesis of Dithioglycoluril

Dithioglycoluril of Formula (4b) was synthesized according to the methoddescribed in Non-Patent Document 4: Tetrahedron Letters, 56, 6085-6088(2015).

Example 1 Synthesis of 1,3,4,6-Tetramethylolmonothioglycoluril

To a 50 mL flask equipped with a cooler, a thermometer, and a stirrer,12.84 g (158.0 mmol) of 37% by mass aqueous formaldehyde solution(available from Tokyo Chemical Industry Co., Ltd.) and 0.38 g (7.7 mmol)of 0.5 N aqueous sodium hydroxide solution were added, and the mixturewas heated to 40° C. and stirred. At the same temperature, 5.00 g (31.6mmol) of monothioglycoluril obtained in Synthesis Example 1 was added tothe flask, and the mixture was heated to 55° C. and stirred for fivehours. The mixture was then cooled to 25° C., and 0.09 g (1.8 mmol) of0.5 N aqueous sodium hydroxide solution was added to the mixture,followed by stirring. Thereafter, 25.00 g of methanol was added to themixture, and the mixture was stirred at 5° C., to thereby precipitatecrystals. The precipitated crystals were filtered and washed with 5.00 gof methanol twice. The resultant residue was dried under reducedpressure, to thereby produce 6.27 g of1,3,4,6-tetramethylolmonothioglycoluril of Formula (2a) as a whitesolid. The yield was 71.3%, and the purity was 100% as determined byhigh-performance liquid chromatography (hereinafter abbreviated as“HPLC”).

The produced 1,3,4,6-tetramethylolmonothioglycoluril showed 6 values of¹H-NMR spectra (DMSO-d₆) as follows.

δ: 6.06 (dd, 4H), 5.72 (s, 2H), 5.19 (dd, 2H), 5.12 (dd, 2H), 4.84 (dd,2H), 4.72 (dd, 2H).

Example 2 (Synthesis of1,3,4,6-Tetrakis(methoxymethyl)monothioglycoluril)

To a 50 mL flask equipped with a cooler, a thermometer, and a stirrer,3.00 g (10.8 mmol) of 1,3,4,6-tetramethylolmonothioglycoluril producedin Example 1, 6.91 g of methanol, and 0.23 g (2.4 mmol) of 65% by massnitric acid were added, and the mixture was heated to 40° C. and stirredfor 25 hours. Thereafter, the mixture was cooled to 25° C., and 0.49 g(2.4 mmol) of 20% by mass aqueous sodium hydroxide solution was added tothe mixture. The solvent was distilled off under reduced pressure at 40°C. To the resultant concentrate, 30.00 g of ethyl acetate was added. Themixture was filtered and washed with 3.00 g of ethyl acetate twice, andthe solvent was distilled off under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/n-heptane=3/1 (by volume)), to thereby produce 2.39 g of1,3,4,6-tetrakis(methoxymethyl)monothioglycoluril of Formula (2b-1) as awhite solid. The yield was 66.4%, and the purity was 100% as determinedby HPLC.

FIG. 1 shows ¹H-NMR spectra of the produced1,3,4,6-tetrakis(methoxymethyl)monothioglycoluril. The 6 values of theNMR spectra (DMSO-d₆) were as follows.

δ: 5.74 (s, 2H), 5.21 (d, 2H), 5.11 (d, 2H), 4.75 (d, 2H), 4.71 (d, 2H),3.26 (s, 6H), 3.20 (s, 6H).

Example 3 Synthesis of 1,3,4,6-Tetramethyloldithioglycoluril

To a 50 mL flask equipped with a cooler, a thermometer, and a stirrer,0.70 g (8.6 mmol) of 37% by mass aqueous formaldehyde solution(available from Tokyo Chemical Industry Co., Ltd.), 0.023 g (0.46 mmol)of 0.5 N aqueous sodium hydroxide solution, and 1.50 g of water wereadded, and the mixture was heated to 40° C. and stirred. At the sametemperature, 0.30 g (1.7 mmol) of dithioglycoluril obtained in SynthesisExample 2 was added to the flask, and the mixture was heated to 55° C.and stirred for one hour. Thereafter, the mixture was cooled to 25° C.,and 1.50 g of methanol was added to the mixture, to thereby precipitatecrystals. The precipitated crystals were filtered and washed with 0.60 gof methanol twice. The resultant residue was dried under reducedpressure, to thereby produce 0.30 g of1,3,4,6-tetramethyloldithioglycoluril of Formula (3a) as a white solid.The yield was 59.6%, and the purity was 100% as determined by HPLC.

The produced 1,3,4,6-tetramethyloldithioglycoluril showed 6 values of¹H-NMR spectra (DMSO-d₆) as follows.

δ: 6.18 (t, 4H), 5.95 (s, 2H), 5.18 (d, 8H).

Example 4 (Synthesis of 1,3,4,6-Tetrakis(methoxymethyl)dithioglycoluril)

To a 50 mL flask equipped with a cooler, a thermometer, and a stirrer,0.29 g (1.0 mmol) of 1,3,4,6-tetramethyloldithioglycoluril produced inExample 3, 1.32 g (41.2 mmol) of methanol, and 0.049 g (0.5 mmol) of 65%by mass nitric acid were added, and the mixture was heated to 40° C. andstirred for 34 hours. Thereafter, the mixture was cooled to 25° C., and0.14 g (0.7 mmol) of 20% by mass aqueous sodium hydroxide solution wasadded to the mixture. The solvent was distilled off under reducedpressure at 40° C. To the resultant concentrate, 2.6 g of pure water wasadded, to thereby precipitate crystals. The precipitated crystals werefiltered and washed with 1.3 g of pure water twice. The resultantresidue was dried under reduced pressure, to thereby produce 0.13 g of1,3,4,6-tetrakis(methoxymethyl)monothioglycoluril of Formula (3b-1) as awhite solid. The yield was 36.9%, and the purity was 97.1% as determinedby HPLC.

FIG. 2 shows ¹H-NMR spectra of the produced1,3,4,6-tetrakis(methoxymethyl)dithioglycoluril. The 6 values of the NMRspectra (DMSO-d₆) were as follows.

δ: 5.98 (s, 2H), 5.21 (d, 4H), 5.15 (d, 4H), 3.27 (s, 12H).

FIG. 3 shows UV spectra of1,3,4,6-tetrakis(methoxymethyl)monothioglycoluril (hereinafterabbreviated as “TMOM-TGU”) produced in Example 2,1,3,4,6-tetrakis(methoxymethyl)dithioglycoluril (hereinafter abbreviatedas “TMOM-DTGU”) produced in Example 4, and commercially available1,3,4,6-tetrakis(methoxymethyl)glycoluril (product name: POWDERLINK1174,hereinafter abbreviated as “TMOM-GU”) as Comparative Example.

As is clear from the results shown in FIG. 3, the thioglycolurilcompound according to the present invention exhibits a shift of UVabsorption wavelength as compared with the sulfur atom-free glycoluril,and has UV absorption around 248 nm.

In order to examine the solubilities of TMOM-TGU produced in Example 2,TMOM-DTGU produced in Example 4, and TMOM-GU as Comparative Example,these compounds were dissolved in propylene glycol 1-monomethyl ether(PGME) or propylene glycol 1-monomethyl ether 2-acetate (PGMEA), each ofwhich is a solvent commonly used in, for example, production processesfor semiconductor devices. The results are shown in Table 1.

As is clear from the results shown in Table 1,1,3,4,6-tetrakis(methoxymethyl)monothioglycoluril exhibits particularlyexcellent solubility in a solvent, since it has an asymmetric molecularstructure and thus low molecular symmetry.

TABLE 1 Comparative Examples Example

Solubility 100 20 20 (g/100 g-PGME) Solubility 100 25 12.5 (g/100g-PGMEA)

INDUSTRIAL APPLICABILITY

The thioglycoluril compound according to the present invention isexpected to be useful as, for example, a crosslinking agent for epoxyresins. In addition, the thioglycoluril compound according to thepresent invention has absorption at the wavelength of KrF eximer laserand thus is useful as a crosslinking agent for an anti-reflectivecoating-forming composition.

The invention claimed is:
 1. A method for producing a dithioglycolurilcompound, the method comprising a first step of causing a reactionbetween formaldehyde and a compound of the following Formula (4b) in abasic aqueous solution, and then isolating a compound of the followingFormula (3a); and a second step of causing a reaction between thecompound of the following Formula (3a) and an alcohol of the followingFormula (5) in an acidic solution containing the alcohol as a solvent,adding a basic aqueous solution to the resultant reaction mixture, andwashing the resultant product with water for removal of impurities fromthe product, so as to produce a dithioglycoluril compound of thefollowing Formula (3b):

(wherein four R¹s are each a linear, branched, or cyclic alkyl grouphaving a carbon atom number of 1 to 4, a phenyl group, a naphthyl group,a benzyl group, or a C₃₋₉ alkyl group having at least one ether bond onthe main chain).